Urinary tract malformations, obstructive uropathy, and hypoplasia/dysplasia are extremely important in terms of pediatric health care costs, with end-stage renal failure in children estimated to cost >$15 billion annually in the United States alone. Even so, little is known regarding the mechanisms that control these processes. Identified was a unique mutant mouse model that develops in utero megabladder, resulting in variable hydroureteronephrosis and chronic renal failure secondary to obstructive uropathy. These animals, designated mgb for megabladder, possess a primary defect in bladder smooth muscle development that is apparent by embryonic day 15. The mgb mouse represents an excellent model for the study of normal and pathogenic bladder development, including the postnatal progression of chronic renal failure that results from the development of in utero obstructive uropathy.

Congenital obstructive nephropathy (CON) is the most common cause of chronic renal failure in children, often leading to end stage renal disease. The megabladder (mgb) mouse exhibits signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure following birth. This study examined the development of progressive renal injury in homozygous mgb mice (mgb−/−). Renal ultrasound was utilized to stratify the disease state of mgb−/− mice, while surgical rescue was performed using vesicostomy. The progression of renal injury was characterized using a series of pathogenic markers including α-smooth muscle isoactin (α-SMA), TGF-β1, connective tissue growth factor (CTGF), E-cadherin, F4/80, Wilm’s Tumor 1 (WT-1), and paired box gene 2 (Pax2). This analysis indicated that mgb−/− mice are born with pathologic changes in kidney development that progressively worsen in direct correlation with the severity of hydronephrosis. The initiation and pattern of fibrotic development observed in mgb−/− kidneys appeared distinctive from prior animal models of obstruction. These observations suggest that the mgb mouse represents a unique small animal model for the study of CON.

In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients.

Disorders of the urinary tract represent a major cause of morbidity and impaired quality of life. To better understand the morphological events responsible for normal urinary tract development, we performed 3-D reconstructive analysis of developing mouse bladders in control, mgb−/−, and Fgfr2Mes−/− mice. Detrusor smooth muscle differentiation initiated in the bladder dome and progressed caudally with the leading edge extending down the right posterior surface of the bladder. Gender-specific differences in detrusor smooth muscle development were observed during early embryonic development. Bladder trigone morphology transitioned from an isosceles to equilateral triangle during development due to the preferential lengthening of the urethra to ureter distance. The primary defect observed in mgb−/− bladders was a significant reduction in detrusor smooth muscle differentiation throughout development. Deviations from normal trigone morphology correlated best with VUR development in Fgfr2Mes−/− mice, while alterations in intravesicular tunnel length did not. In conclusion, multivariate morphometric analysis provides a powerful tool to quantify and assess urinary tract development.

Recent studies in our lab identified a mutant mouse model of obstructive nephropathy designated mgb for megabladder. Homozygotic mgb mice (mgb؊/؊) develop lower urinary tract obstruction in utero due to a lack of bladder smooth muscle differentiation. This defect is the result of a random transgene insertion/translocation into chromosomes 11 and 16. Transcriptional profiling identified a significantly over-expressed cluster of gene products located on the translocated fragment of chromosome 16 including urotensin II-related peptide (Urp), which was shown to be preferentially over-expressed in developing mgb؊/؊ bladders. Pathway analysis of mgb microarray data indicated dysregulation of at least 60 gene products associated with smooth muscle development. In conclusion, the results of this study indicate that the molecular pathways controlling normal smooth muscle development are severely altered in mgb؊/؊ bladders, and provide the first evidence that Urp may play a critical role in bladder smooth muscle development. Developmental Dynamics 237:170 -186, 2008.